Aβ peptides can enter the brain through a defective blood-brain barrier and bind selectively to neurons

Peter M. Clifford, Shabnam Zarrabi, Gilbert Siu, Kristin J. Kinsler, Mary C. Kosciuk, Venkateswar Venkataraman, Michael R. D'Andrea, Steven Dinsmore, Robert G. Nagele

Research output: Contribution to journalArticlepeer-review

118 Scopus citations

Abstract

We have investigated the possibility that soluble, blood-borne amyloid beta (Aβ) peptides can cross a defective blood-brain barrier (BBB) and interact with neurons in the brain. Immunohistochemical analyses revealed extravasated plasma components, including Aβ42 in 19 of 21 AD brains, but in only 3 of 13 age-matched control brains, suggesting that a defective BBB is common in AD. To more directly test whether blood-borne Aβ peptides can cross a defective BBB, we tracked the fate of fluorescein isothiocyanate (FITC)-labeled Aβ42 and Aβ40 introduced via tail vein injection into mice with a BBB rendered permeable by treatment with pertussis toxin. Both Aβ40 and Aβ42 readily crossed the permeabilized BBB and bound selectively to certain neuronal subtypes, but not glial cells. By 48 h post-injection, Aβ42-positive neurons were widespread in the brain. In the cerebral cortex, small fluorescent, Aβ42-positive granules were found in the perinuclear cytoplasm of pyramidal neurons, suggesting that these cells can internalize exogenous Aβ42. An intact BBB (saline-injected controls) blocked entry of blood-borne Aβ peptides into the brain. The neuronal subtype selectivity of Aβ42 and Aβ40 was most evident in mouse brains subjected to direct intracranial stereotaxic injection into the hippocampal region, thereby bypassing the BBB. Aβ40 was found to preferentially bind to a distinct subset of neurons positioned at the inner face of the dentate gyrus, whereas Aβ42 bound selectively to the population of large neurons in the hilus region of the dentate gyrus. Our results suggest that the blood may serve as a major, chronic source of soluble, exogenous Aβ peptides that can bind selectively to certain subtypes of neurons and accumulate within these cells.

Original languageEnglish (US)
Pages (from-to)223-236
Number of pages14
JournalBrain Research
Volume1142
Issue number1
DOIs
StatePublished - Apr 20 2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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